The present invention relates to a potassium channel (K+-channel) activator comprising a pyrrole derivative or its pharmaceutically acceptable salt as an active ingredient. A potassium channel activator is useful for the prophylaxis or therapy of K+-channel-associated physiologic disorders.
The potassium channel exists in a variety of cells such as nerve cells and smooth muscle cells and is involved in various physiological processes and control the homeostasis of normal cell ions. Generally potassium ions regulate the resting membrane potential of cells, and an efflux of potassium ions following depolarization of the cell membrane results in repolarization of the membrane. The potassium channel activator causes hyperpolarization of cells. Thereby, in nerve cells, suppress cellular activity to reduce the transmitters release from the nerve endings and, in smooth muscle cells, suppress the contractility.
Therefore, a potassium channel activator is considered to be of value in the therapy of nervous system disorders inducing spasmodic or ischemic responses through its action on nerve cells. Furthermore, through its action on smooth muscle cells, a potassium channel activator is expected to be useful in the therapy of various diseases such as hypertension, angina pectoris, asthma and irritable bowel syndrome.
Already known as compounds having potassium channel activating activity are benzopyran derivatives (Japanese Laid-Open S58-67683, Japanese Laid-Open H6-25233, WO 94/13297, etc.), thienopyran derivatives (WO 94/13297 etc.), benzoxazine derivatives (Japanese Laid-Open H5-70464, WO 94/13297, etc.), benzoxepine derivatives (WO 94/13297 etc.), quinoline derivatives (WO 94/13297 etc.), indole derivatives (WO 94/13297 etc.), benzocycloheptane derivatives (WO 94/13297 etc.) and pyridine derivatives (The Merck Index, 11th edition, 7407), among others.
The compound according to the present invention (hereinafter referred to as the compound of the invention) is a pyrrole derivative which is structurally different from any of the above-mentioned compounds having potassium channel activating activity. It has not heretofore been known that a pyrrole derivative ever has potassium channel activating activity.
The object of the present invention is to provide a novel potassium channel activator.
Exploring into various compounds with enthusiasm, the inventors of the present invention found surprisingly that a pyrrole derivative of the following general formula [1] has potassium channel activating activity and have completed this invention.
The present invention, therefore, is directed to a potassium channel activator composition comprising a pyrrole derivative of the following general formula [1] or a pharmaceutically acceptable salt thereof as an active ingredient. 
wherein R1 represents hydrogen or alkoxycarbonylamino;
R2 represents (i) alkyl, (ii) aryl which may be substituted, (iii) aromatic heterocyclyl which may be substituted, (iv) a group of the following formula [2]
[wherein R6 and R7 may be the same or different and each represents (1) hydrogen or (2) alkyl (said alkyl may be substituted by (1) aryl which may be substituted by alkoxy, (2) aromatic heterocyclyl, or (3) hydroxy)], or (v) a group of the following formula [3]
Z1 and Z2 may be the same or different and each represents xe2x80x94CH2xe2x80x94 or  greater than Cxe2x95x90O; provided that Z1 and Z2 do not concurrently represent  greater than Cxe2x95x90O;
Y represents xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or  greater than NR9;
R9 represents hydrogen, alkyl, acyl, aryl, or aromatic heterocyclyl;
m represents an integer of 1-3; n represents an integer of 0-2; p represents 0 or 1;
in case R2 represents aryl which is substituted or aromatic heterocyclyl which is substituted, the particular aryl or aromatic heterocyclyl may be substituted by 1-3 same or different members selected from the group consisting of (1) halogen, (2) alkyl which may be substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (said alkoxy may be substituted by (1) halogen, (2) aryl which may be substituted by alkoxy, or (3) alkoxy), (8) xe2x80x94NHSO2R82, and (9) xe2x80x94NR83R84; or two adjacent substituent groups may jointly represent xe2x80x94Oxe2x80x94(CH2)txe2x80x94Oxe2x80x94 (t represents 1 or 2);
R82 represents (1) alkyl or (2) aryl which may be substituted by alkyl;
R83 and R84 may be the same or different and each represents (1) hydrogen, (2) alkyl, or (3) acyl; or R83 and R84 jointly and taken together with the adjacent N atom represent 5- through 7-membered cyclic amino;
R3 represents cyano or carbamoyl;
R4 represents hydrogen or alkyl;
E represents alkylene; q represents 0 or 1;
A represents (1) methyl, (2) aryl which may be substituted, or (3) aromatic heterocyclyl which may be substituted;
in case A represents aryl which is substituted or aromatic heterocyclyl which is substituted, the particular aryl or aromatic heterocyclyl may be substituted by 1-3 same or different members selected from the group consisting of (1) halogen, (2) alkyl which may be substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (said alkoxy may be substituted by (1) halogen, (2) aryl which may be substituted by alkoxy, or (3) alkoxy), (8) xe2x80x94NHSO2R92, and (9) xe2x80x94NR93R94; or two adjacent substituent groups may jointly represent xe2x80x94Oxe2x80x94(CH2)uxe2x80x94Oxe2x80x94 (u represents 1 or 2);
R92 represents (1) alkyl or (2) aryl which may be substituted by alkyl;
R93 and R94 may be the same or different and each represents (1) hydrogen, (2) alkyl, or (3) acyl; or R93 and R94 jointly and taken together with the adjacent N atom represent 5- through 7-membered cyclic amino;
Axe2x80x94(E)q, R4, and the double bond of the pyrrole ring may jointly, i.e. 
X represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or  greater than NR90 where R90 represents alkyl;
R95, R96 and R97 may be the same or different and each is selected from the group consisting of (1) hydrogen, (2) halogen, (3) alkyl which may be substituted by halogen, (4) cyano, (5) nitro, (6) alkoxycarbonyl, (7) hydroxy, (8) alkoxy (said alkoxy may be substituted by halogen or alkoxy), (9) xe2x80x94NHSO2R92 (R92 is as defined above), and (10) xe2x80x94NR93R94 (R93 and R94 are as defined above); any two adjacent substituent groups among R95, R96, and R97 may jointly represent xe2x80x94Oxe2x80x94(CH2)uxe2x80x94Oxe2x80x94 (u is as defined above).
In the context of the present invention, the xe2x80x9calkylxe2x80x9d includes straight-chain or branched-chain alkyl groups containing 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
The xe2x80x9carylxe2x80x9d includes aryl groups of 6-12 carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl, 3-biphenyl and 4-biphenyl.
The xe2x80x9caromatic heterocyclylxe2x80x9d includes groups of aromatic 5- or 6-membered rings containing 1-4 nitrogen, oxygen or sulfur atoms as ring members and the corresponding benzene-fused ring systems (however, 2-pyrrolyl and 3-pyrrolyl are excluded), thus including 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 1-indolyl, 2-indolyl, 3-indolyl, 1-tetrazolyl, 2-furyl, 3-furyl, 2-benzofuranyl, 3-benzofuranyl, 2-thienyl, and 3-thienyl, among others.
The xe2x80x9calkylenexe2x80x9d includes straight-chain or branched groups of 1-4 carbon atoms, such as the following. 
The alkyl moiety of said xe2x80x9calkoxyxe2x80x9d, xe2x80x9calkoxycarbonylxe2x80x9d or xe2x80x9calkoxycarbonylaminoxe2x80x9d includes the alkyl groups mentioned above.
The xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo and iodo.
The xe2x80x9cacylxe2x80x9d includes groups of 1-7 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, isohexanoyl and benzoyl.
The 5-7-membered cyclic amino represented by NR83R84 or NR93R94 includes but is not limited to 1-pyrrolidinyl, 1-piperidinyl and 1-hexamethyleneimino.
The preferred species of the compound [1] of the invention includes the compound in which R1 is hydrogen, R2 is NH2, pyrrolidino or methyl, R3 is cyano, R4 is hydrogen or methyl, q is 0, and A is aryl which may be substituted or a aromatic heterocyclyl which may be substituted.
Particularly preferred examples of the compound [1] of the invention includes the following compounds.
(1) 2-Amino-3-cyano-5-(2-fluorophenyl)-4-methylpyrrole (hereinafter referred to as compound 1)
(2) 2-Amino-3-cyano-4-methyl-5-phenylpyrrole (hereinafter referred to as compound 2)
(3) 2-Amino-5-(3-chlorophenyl)-3-cyano-4-methylpyrrole (hereinafter referred to as compound 3)
(4) 2-Amino-3-cyano-5-(2-furyl)-4-methylpyrrole (hereinafter referred to as compound 4)
(5) 2-Amino-3-cyano-5-(3,4-methylenedioxyphenyl)pyrrole (hereinafter referred to as compound 5)
(6) 2-Amino-3-cyano-5-(2,4-difluorophenyl)pyrrole (hereinafter referred to as compound 6)
(7) 5-(3-Chlorophenyl)-3-cyano-2-methylpyrrole (hereinafter referred to as compound 7)
(8) 2-Amino-3-cyano-4-methyl-5-(3-nitrophenyl)pyrrole (hereinafter referred to as compound 8)
(9) 3-Cyano-2,4-dimethyl-5-phenylpyrrole (hereinafter referred to as compound 9)
(10) 3-Cyano-5-(3-ethoxyphenyl)-2-pyrrolidinopyrrole (hereinafter referred to as compound 10)
(11) 3-Cyano-5-(3,4-methylenedioxyphenyl)-2-pyrrolidinopyrrole (hereinafter referred to as compound 11)
The compound of the invention, represented by general formula [1] above, can be produced by any of the processes described in WO 96/40634.
Among species of the compound of the invention, any compound that is basic can be administered for medication in the free base form but optionally may be converted to a pharmaceutically acceptable salt by the known procedure and administered. The salt includes salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and salts with organic acids such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid.
The compound of the invention has potent activating activity on potassium channel and yet is only slightly toxic as shown in the experimental examples which appear hereinafter, so that it is useful as a prophylactic or therapeutic drug for cardiovascular diseases such as hypertension, ischemic diseases (such as angina pectoris and myocardial infarction), arteriosclerosis, hyperlipemia, congestive heart failure, arrhythmia and peripheral vascular disorders.
In addition, the compound of the invention is useful as a therapeutic drug for various disorders associated with smooth muscle contraction, such as cerebrovascular disorders (e.g. cerebrovascular spasm), peripheral vascular disorders (e.g. trichogenetic insufficiency, psilosis, coldness of limbs, etc.), respiratory disorders (reversible airway obstruction, hypersensitivity airway obstruction, asthma), gastrointestinal disorders (ulcer, irritable bowel syndrome, bile duct obliteration, etc.), visuoauditory disorders (e.g. glaucoma, ocular hypertension, etc.), urinary system disorders (renal failure, disorders accompanied with the passage of renal calculi, etc.), and genital organ disorders (erectile dysfunction, premature labor, etc.).
Furthermore, the compound of the invention is useful as a therapeutic drug for blood sugar abnormalities (hypoglycemia etc.) and as a prophylactic or therapeutic drug for disorders due to abstinence in cases of abuse of such substances as cocaine, nicotine, alcohol, and benzodiazepine, disorders which may be prevented or cured with an anticonvulsant, such as epilepsy, neuropathies arising from cerebrovascular disorders, and various nervous system disorders such as schizophrenia.
For use of the compound of the invention as a medicine, the compound can be administered, either as it is or in the form of a pharmaceutical composition containing it in a concentration of, for example, 0.1-99.5%, preferably 0.5-90%, in a pharmaceutically acceptable, nontoxic and inert carrier, to mammals inclusive of humans.
As the carrier, at least one member selected from solid, semisolid or liquid diluents, fillers and other auxiliary formulating agents is employed. The pharmaceutical composition is preferably administered in a unit dose form. The pharmaceutical composition of the present invention can be administered intravenously, orally, into the target tissue, locally (e.g. transdermally) or rectally. Dosage forms suited to the respective routes of administration should of course be selected. Particularly preferred is oral administration.
Oral administration can be made using a solid or liquid dose unit, such as neat powders, powders, tablets, sugar-coated tablets, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets and so on.
Neat powders can be prepared by comminuting the active substance to a suitable particle size. Powders can be produced by comminuting the active substance to a suitable particle size and blending the resulting particles with a similarly comminuted pharmaceutical carrier, such as fine particles of, for example, an edible carbohydrate such as starch or mannitol. Where necessary, flavoring agents, preservatives, dispersants, coloring agents, perfumes, etc. can also be added and mixed.
Capsules can be produced by filling capsule shells, such as gelatin capsule shells, with such comminuted neat powders or powders or granules prepared therefrom as described below for the manufacture of tablets. Prior to filling, a lubricant or fluidizing agent, such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, etc., can be added to the powdery material. Furthermore, the bioavailability of the medicament after intake of the capsule can be improved by adding a disintegrator or solubilizer, such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substitution-degree hydroxypropylcellulose, croscarmellose sodium, carboxymethylstarch sodium, calcium carbonate, sodium carbonate and so on.
The finely divided powder mentioned above may be dispersed in a vegetable oil, polyethylene glycol, glycerin or a surfactant and the resulting suspension be wrapped in gelatin sheets to provide soft capsules. Tablets can be produced by preparing a powdery mixture using an excipient, granulating or slugging it, adding a disintegrator or a lubricant, and compressing the mixture. The powdery mixture can be prepared by mixing a suitably comminuted powder of the active substance with said diluent or base and, where necessary, adding a binder (e.g. carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.), a dissolution retardant (e.g. paraffin), a reabsorption agent (e.g. a quaternary salt) and an adsorbent (e.g. bentonite, kaolin, dicalcium phosphate). The powdery mixture may be processed into granules by wetting it with a binder, such as a syrup, starch paste, gum arabic, a cellulose solution or a polymer solution, in the first place, stirring the mixture, drying it, and pulverizing it. Instead of granulating the powder, it may be compressed with a tablet machine in the first place and crushing the crude-form slugs into granules.
The granules thus obtained can be protected against interadhesion by adding a lubricant such as stearic acid, a stearate, talc, mineral oil or the like. The lubricated mixture is then compressed. Bare tablets thus obtained can be film-coated or sugar coated.
The drug may be admixed with a free-flowing inert carrier and directly compressed into tablets without said granulation or slugging operation. A transparent or translucent protective film comprising a hermetic shellac coat, a sugar or polymer covering film, or a polished wax top coat may also utilized.
Other oral dosage forms, such as a solution, a syrup and an elixir, can also be provided as a unit dose form containing a predetermined amount of the drug in a given quantity. Syrups can be produced by dissolving the compound in suitable flavored aqueous solutions, while elixirs can be produced by using nontoxic alcoholic vehicles. Suspensions can be formulated by dispersing the compound in nontoxic vehicles. Where necessary, solubilizers and emulsifiers (e.g. ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester), preservatives and flavoring agents (e.g. peppermint oil, saccharin), among others, may also be added.
If necessary, unit dose formulations for oral administration may be microencapsulated. Such formulations may be coated or embedded in a high polymer or a wax for prolonging the duration of action or insuring a sustained release.
Administration into the target tissue can be made using a liquid unit dosage form suited for subcutaneous, intramuscular or intravenous administration, for example a solution or a suspension. Such dosage forms can be produced by suspending or dissolving a predetermined amount of the compound in an injectable nontoxic liquid vehicle such as an aqueous medium or an oily medium and, then, sterilizing the suspension or solution. For isotonizing such parenteral products, nontoxic salts or salt solutions may be added. A stabilizer, a preservative and/or an emulsifier may also be incorporated.
Rectal administration can be made using suppositories manufactured by dissolving or suspending the compound in a low-boiling water-soluble or insoluble solid, such as polyethylene glycol, cacao butter, a semisynthetic oil (e.g. Witepsol(trademark)), a higher ester (e.g. myristyl palmitate) or a mixture thereof.
The dosage as a potassium channel activator is preferably established with reference to the nature and severity of disease, patient factors such as age and body weight, the route of administration, etc. but the usual daily dose is 0.1-1000 mg/adult patient, preferably 1-500 mg/adult patient, in terms of the compound of the invention.
Dosage reduction may be warranted in some cases, while dosage escalation may be needed in others. Moreover, the above dosage may be administered in 2-3 divided doses a day.